HK1078309A - Method for the production of crystalline forms and crystalline forms of optical enantiomers of modafinil - Google Patents
Method for the production of crystalline forms and crystalline forms of optical enantiomers of modafinil Download PDFInfo
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Description
The invention relates to a process for obtaining a crystalline form of the enantiomers of modafinil. The application describes the crystalline forms that can be obtained according to this process.
The application describes a new process for preparing the optical enantiomers of modafinil from (±) modafinic acid.
U.S. Patent 4,177,290 describes modafinil in the racemic form, also known as (±) 2-(benzhydrylsulfinyl)acetamide or (±) 2-[(diphenylmethyl)sulfinyl] acetamide, as a compound having central nervous system stimulating properties.
U.S. Patent 4,927,855 describes the two optical enantiomers of modafinil. It particularly describes the levorotatory enantiomer and its use as an antidepressant or stimulant agent in the treatment of hypersomnia and Alzheimer's disease-related disorders. The process for preparing the two optical enantiomers of modafinil from (±) modafinic acid or (±)-benzhydrylsulfinylacetic acid, described in this document, is illustrated in the following synthesis scheme:
This process involves, in a first step, the separation of the optical enantiomers of (±)-modafinic acid by forming diastereomers with the optically active agent α-methylbenzylamine.
The (-)-benzhydrylsulfinylacetate of (-)-α-methylbenzylamine is then converted by acid hydrolysis into (-)-benzhydrylsulfinylacetic acid. This compound is subsequently esterified in the presence of dimethyl sulfate and then amidated in the presence of ammonia (gas). The (-) enantiomer or levorotatory form of modafinil is obtained by this process with a overall yield of 5.7% relative to (±)-modafinic acid, calculated based on the yields corresponding to each step.
Day et al. (Chem. Commun., 2006, 54-56) studied the latent polymorphism of maleic acid, and reported the discovery of a second crystalline polymorph of maleic acid.
Dziubek et al. (J. Am. Chem. Soc., 2007, 129, 12620-12621) investigate quasi-isostructural polymorphs of ethynylbenzene, particularly focusing on the resolution of the CH(alkyne)-π(arene) and cooperative CH(alkyne)-π(alkyne) interactions by pressure freezing.
Sanphui et al. (Chem. Commun., 2011, 47, 5013-5015) disclose two new crystalline polymorphs and an amorphous phase of curcumin. Polymorph 2 is described as having a higher dissolution rate and better solubility than the known polymorph 1.
The invention relates to a process for preparing a polymorphic form of the levorotatory or dextrorotatory enantiomer of modafinil, characterized in that it produces an X-ray diffraction pattern comprising lines of intensity at lattice distances: 8.54; 4.27; 4.02; 3.98 (Å), said process comprising the following steps: i) dissolving one of the optical enantiomers of modafinil in a solvent selected from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, 2-methyl-2-pentanol, 1,2-propanediol, t-amyl alcohol, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, ethyl formate, diethyl ether, tetrahydrofuran, dioxane, dibutyl ether, isopropyl ether, t-butyl methyl ether, tetrahydropyran, chloroform, 1,2-dichloroethane, dichloromethane, chlorobenzene, o-xylene, m-xylene, p-xylene, a mixture of o-xylene, m-xylene and/or p-xylene, methoxybenzene, nitrobenzene, trifluorotoluene, toluene, acetone, methyl ethyl ketone, methyl isobutyl ketone, butan-2-one, cyclopentanone, isobutyl methyl ketone, 2-pentanone, 3-pentanone, acetic acid, pyridine, acetonitrile, propionitrile, 4-methylmorpholine, N,N-dimethylacetamide, nitromethane, triethylamine, N-methylpyrrolidone, heptane, 2,2,4-trimethylpentane, cyclopentane, cyclohexane, dimethyl carbonate, water, and alcohol/water mixtures; ii) crystallizing the enantiomer of modafinil; iii) recovering the crystalline form of the modafinil enantiomer thus obtained.
The term "enantiomer" refers to stereoisomers that are mirror images of each other and not superimposable. Enantiomers are typically designated either by (+) and (-) or by (d) and (l), indicating an optical rotation at the chiral center.
Stereoisomerism can also be denoted either by (D) and (L) or by (R) and (S), which are descriptions of the absolute configuration.
In the following, the levorotatory enantiomer of modafinil will be arbitrarily referred to as the l-enantiomer or (-), while the dextrorotatory enantiomer will be referred to as the d-enantiomer or (+).
It has now been discovered a process for obtaining different crystalline forms of the optical enantiomers of modafinil. More specifically, the inventors have shown that the crystalline form obtained mainly depends on the nature of the recrystallization solvent used.
The term "crystalline form" refers indiscriminately, in the sense of the present description, to a polymorphic form or a solvate.
By "polymorphic form," we mean an organized structure consisting only of solute molecules, possessing a characteristic crystal fingerprint.
The term "solvate" refers to an organized structure having a characteristic crystal lattice that involves both solute molecules and solvent molecules. Solvates that involve one solute molecule for each solvent molecule are called true solvates.
In addition, the inventors have shown that the l-modafinil and d-modafinil prepared under the conditions described in U.S. Patent No. 4,177,290 are obtained in the form of a single polymorphic form designated as Form I, which corresponds to the thermodynamically most stable polymorphic form under normal temperature and pressure conditions. The Declaration of Dr. John Mallamo, filed on March 22, 2012, within the framework of the examination procedure for the application on which the present patent is based, indicates that U.S. Patent No. 4,177,290 relates to a racemate of modafinil, and that the preparation methods described therein produce a racemic mixture of modafinil. It confirms that U.S. Patent No. 4,177,290 does not relate to individual enantiomers of modafinil. Form I exhibits the X-ray diffraction pattern below, in which 'd' represents the interplanar spacing and the ratio (I/Io) represents the relative intensity.
| CRL 40982 FORME I | ||
| 2 Theta (degrés) | d (Å) | I/Io (%) |
| 9.8 | 13.40 | 32 |
| 15.4 | 8.54 | 87 |
| 20.8 | 6.34 | 24 |
| 26.4 | 5.01 | 14 |
| 28.3 | 4.68 | 19 |
| 28.7 | 4.62 | 16 |
| 29.9 | 4.44 | 45 |
| 31.1 | 4.27 | 100 |
| 31.6 | 4.20 | 23 |
| 32 | 4.15 | 14 |
| 33.1 | 4.02 | 78 |
| 33.4 | 3.98 | 84 |
| 34.1 | 3.90 | 16 |
| 35.1 | 3.80 | 15 |
| 39 | 3.43 | 22 |
| Diffractomètre: Miniflex Rigaku (Elexience) |
The crystalline forms of a given compound generally exhibit very distinct physical, pharmaceutical, physiological, and biological properties from each other.
In this sense, the crystalline forms of optically active modafinil, particularly the polymorphic forms, are interesting because they exhibit advantageous and different characteristics compared to form I.
It has now been discovered a new method for preparing the optical enantiomers of modafinil from (±)-modafinic acid, said method allowing the isolation of each enantiomer with yields and optical purity significantly higher than those described in US Patent 4,927,855.
In a particularly advantageous manner, a process has now been developed for separating the two optical enantiomers of (±)-modafinic acid by preferential crystallization, advantageously applicable on a preparative scale.
This method of doubling the acid (±)-modafinic presents many advantages: it avoids the use of an expensive intermediate chiral agent, whose subsequent preparation usually involves losses rarely below 10% (De Min., M., Levy, G. and Micheau J.-C., 1988; J. Chem. Phys. 85, 603-19); both enantiomers are obtained directly, unlike the classical resolution method involving the formation of diastereomeric salts; the yield is theoretically quantitative due to the successive recycles of the mother liquors; the purification of the crude enantiomer crystals is easy.
The invention therefore aims to provide a process for preparing the crystalline forms of the enantiomers of modafinil.
The invention also aims to propose a new process for preparing the optical enantiomers of modafinil, and notably the levorotatory enantiomer of modafinil.
These and other objects are achieved by the present invention. The application describes a process for preparing crystalline forms of the optical enantiomers of modafinil, comprising the following steps: i) dissolving one of the optical enantiomers of modafinil in a solvent other than ethanol; ii) crystallizing said modafinil enantiomer; and iii) recovering the crystalline form of said modafinil enantiomer thus obtained.
In the context of the present application, the solvent used at step i) of the process, also referred to as "recrystallization solvent," is a solvent capable of ensuring the crystallization of the said optical enantiomer of modafinil, preferably at atmospheric pressure. In other words, it is any solvent A capable, at a given pressure, of forming, within a first temperature and concentration range, a single-phase system comprising at least one of the enantiomers in a diluted solution in solvent A; and within a second, distinct temperature and concentration range, a second two-phase system comprising crystals of the said enantiomer in the presence of a saturated solution. The two ranges are separated from each other by the solubility curve of the said enantiomer T (°C) = f (concentration of enantiomer) at the considered pressure.
In general, the crystallization of step ii) consists of transitioning from the single-phase system to the two-phase system by varying the temperature and concentration.
As examples of solvents that may be suitable for the recrystallization process according to the request, one can particularly mention alcoholic solvents, carboxylic acid ester solvents, ether solvents, chlorinated solvents, aromatic solvents, and lower aliphatic ketone solvents. Other solvents include carboxylic acid solvents, aprotic polar solvents, alicyclic hydrocarbons, aliphatic hydrocarbons, carbonates, heteroaromatics, and water.
Among the alcoholic solvents, there are notably lower alkyl alcohols such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, 2-methyl-2-pentanol, 1,2-propanediol, and amyl alcohol. Methanol, propanol, and isopropanol are particularly preferred.
Among ester-type solvents, one can mention alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and alkyl formates such as ethyl formate, with ethyl acetate being particularly preferred.
They are useful as ether solvents for recrystallization, diethyl ether, tetrahydrofuran (THF), dioxane, dibutyl ether, isopropyl ether, t-butyl methyl ether, tetrahydropyran, with tetrahydrofuran being particularly preferred.
Among the chlorinated solvents, one can mention chlorinated hydrocarbons, such as chloroform, 1,2-dichloroethane, dichloromethane, and chlorinated aromatics such as chlorobenzene.
As examples of aromatic solvents, o-xylene, m-xylene, p-xylene, or a mixture of o-xylene, m-xylene, and p-xylene, methoxybenzene, nitrobenzene, trichlorotoluene, toluene, with o-xylene, m-xylene, and p-xylene being particularly preferred.
Ketonic solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, butan-2-one, cyclopentanone, isobutyl methyl ketone, 2-pentanone, and 3-pentanone are useful as solvents.
As an example of a carboxylic acid solvent, acetic acid can be specifically mentioned.
As an example of a heteroaromatic solvent, pyridine can be specifically mentioned.
Examples of aprotic polar solvents include acetonitrile, propionitrile, 4-methylmorpholine, N,N-dimethylacetamide, nitromethane, triethylamine, and N-methylpyrrolidone (NMP).
Examples of aliphatic hydrocarbons include heptane, 2,2,4-trimethylpentane.
Examples of alicyclic hydrocarbons include cyclopentane, cyclohexane.
Examples of carbonates include alkyl carbonates such as dimethyl carbonate.
According to a preferred embodiment of the method according to the invention, the crystallization solvents are selected from acetone, methanol, 1,4-dioxane, ethyl acetate, mixtures of ortho-, meta-, and paraxylene, isopropanol, n-propanol, dimethyl carbonate, tetrahydrofuran, chloroform, methyl ethyl ketone, water, and alcohol/H2O mixtures.
Thus, the crystalline forms of the optical enantiomers of modafinil can be obtained by recrystallization of the enantiomers in certain solvents, whose nature and possibly the crystallization conditions mainly determine the type of crystalline form obtained.
The recrystallization solvent, through its interaction with functional groups and electron-withdrawing or electron-donating substituents, can indeed favor certain molecular arrangements that will give rise to a specific crystalline form under given crystallization conditions.
Generally, the recrystallization solvent used in step i) is heated, preferably under reflux, until complete dissolution of the optical enantiomer of modafinil in the solvent is achieved. If the concentration of the optical enantiomer of modafinil at step i) is not a critical factor for crystallization, it is nevertheless preferred to operate with a concentration of the optical enantiomer of modafinil close to the solubility limit in the considered recrystallization solvent.
According to one method of implementation, the optical enantiomer of modafinil is dissolved by heating the solvent under reflux, and then an additional amount of said optical enantiomer is added in portions in order to reach saturation. Additional solvent may be added to ensure complete dissolution.
According to another embodiment, the optical enantiomer of modafinil is suspended in the heated solvent, and then an additional amount of solvent is added in portions in order to obtain a homogeneous solution and thus reach saturation.
The crystallization process of the optical enantiomer of modafinil at step ii) can be accelerated according to techniques known to those skilled in the art, such as cooling the solution, evaporating part of the solvent, adding an antisolvent, or seeding the solution with crystals of optically active modafinil having the same crystalline form as the one expected. Usually, the mixture is kept under agitation throughout the crystallization process, in order to obtain a homogeneous suspension and a rapid renewal of the mother liquor around each crystal.
The crystallization process of the method according to the invention can be carried out under thermodynamic or kinetic conditions.
In the sense of the present description, "crystallization under thermodynamic conditions" refers to a crystallization carried out under conditions where the equilibrium between the homogeneous solution, on the one hand, and the saturated solution in the presence of l- or d-modafinil crystals, on the other hand, is maintained.
For example, a thermodynamic crystallization can be carried out by slowly cooling the solution obtained at step i), typically by allowing the solution to cool to room temperature or by applying a cooling rate or ramp lower than or equal to 0.75°C/min, preferably 0.6°C, and more preferably 0.5°C/min.
By "crystallization carried out under kinetic conditions," as used in the present description, is meant a crystallization in which the equilibrium between the homogeneous solution, on one hand, and the saturated solution in the presence of crystals of d or l-modafinil, on the other hand, is abruptly shifted toward this latter two-phase domain, i.e., toward crystal formation.
As an example, a so-called kinetic crystallization can be achieved, for instance, by rapid cooling, such as applying a cooling ramp of 300°C/min, or by precipitation through the addition of an antisolvent to the solution obtained at step i).
For illustrative purposes, these two types of thermodynamic or kinetic crystallization are achieved in the present description by slow or rapid cooling.
Of course, any other crystallization technique such as solvent evaporation or precipitation, which allows to place the system under kinetic and/or thermodynamic conditions, also falls within the scope of the process according to the invention.
Thus, according to a particular method of implementation, crystallization at step ii) can be carried out by precipitation, optionally in the presence of crystal seeds of the desired crystalline form.
The inventors also showed that certain solvents can lead to crystalline forms, more specifically to polymorphic forms, which are distinct depending on whether crystallization is carried out under kinetic or thermodynamic conditions.
According to a preferred method of implementation, crystallization consists of cooling the solution obtained in step i).
In any case, according to a first method, the cooling is rapid and generally corresponds to quenching the solution obtained in step i) in a bath at a temperature lower than or equal to 0°C, such as an ice water bath, for a sufficient time to allow complete crystallization of the solution, or alternatively to cooling with a cooling ramp, for example between -1°C and -5°C per minute.
According to a second embodiment, the cooling is slow. In this context, the solution is generally allowed to cool from the solvent's boiling point temperature down to ambient temperature, or the solution is cooled using a cooling ramp preferably between -0.1°C/min and -0.8°C/min, and more preferably close to -0.5°C/min, until generally a temperature of 15°C to 20°C.
Among the preferred solvent/antisolvent combinations according to the invention, one can notably mention the combinations water / acetone, acetonitrile / water, ethanol / water, methanol / water, and acetic acid / water.
Finally, the crystalline forms of the optical enantiomers of modafinil can be isolated using classical methods such as filtration and centrifugation.
As an example, the preparation process according to the invention is particularly applied with the levorotatory enantiomer of modafinil.
The crystalline form obtained by this method is a polymorphic form.
It should be noted in this regard that, in general, each of the enantiomers (l) and (d) of a given chemical compound, when recrystallized under the same experimental conditions, lead to crystalline forms, notably polymorphic ones, having identical X-ray powder diffraction patterns.
Regarding this, one may refer notably to the work of J. Bernstein "Polymorphism in Molecular Crystals" 2002, University Press, Oxford, UK, and to the publication of G. Coquerel, Enantiomer, 2000; 5(5): 481-498 ; Gordon and Breach Science Publishers.
For this reason, the dextrorotatory form, whose X-ray diffraction spectra of the crystalline forms are identical to those of the levorotatory form described below and vice versa, is part of the invention.
In the following, the polymorphic forms designated as Form I, II, III, IV and V thus include the CRL40982 forms I, II, III, IV, V obtained from the levorotatory enantiomer and the CRL40983 forms I, II, III, IV, V obtained from the dextrorotatory enantiomer.
In this context, the process using a solvent selected from acetone, ethanol, 1,4-dioxane, ethyl acetate, and mixtures of ortho-, meta-, and para-xylene, followed by a slow cooling crystallization step, leads to the formation of form I or CRL40982 form I.
The process using a solvent selected from methanol, water, or alcohol/water mixtures, in particular methanol/water and ethanol/water, as well as a crystallization step by rapid cooling leads to the obtaining of form I or CRL 40982 Form I.
According to another preferred variant of the invention, the process using methanol and a crystallization step by precipitation through the addition of cold water as an antisolvent for methanol leads to form I.
The request describes a process using a solvent at step i), selected from isopropanol, ethyl acetate, n-propanol, or denatured ethanol in toluene, and a rapid cooling crystallization step leading to a polymorphic form designated as Form II or CRL 40982 Form II.
According to a variant of the process, form II can also be obtained by slow cooling in isopropanol.
It can thus be noted that the formation of form II in isopropanol does not depend on the crystallization conditions (thermodynamic or kinetic).
According to another variant of the process described in the application, the solvent used in step i) is acetone, and step ii) of crystallization consists of rapid cooling, apparently leading to the formation of a polymorphic form designated as form III or CRL 40982 form III.
As a variant of the process described in the application, the solvent used in step i) is selected from tetrahydrofuran, chloroform, and methyl ethyl ketone, and step ii) of crystallization consists of a slow cooling of the solution, thereby obtaining a polymorphic form designated as form IV or CRL 40982 form IV.
The recrystallization process of the optical enantiomers of modafinil may, depending on the nature of the solvent used, lead to the formation of solvates.
As a variant of the process described in the application, the solvent used in step i) is selected from 2-pentanone and tetrahydrofuran, and step ii) of crystallization consists of slow cooling of the solution in 2-pentanone and rapid cooling in THF, thereby obtaining a polymorphic form designated as form V.
When the solvent used in step i) is dimethyl carbonate and the crystallization consists of slow cooling, a dimethyl carbonate solvate of (-)-modafinil is obtained.
When the solvent used in step i) is acetic acid and crystallization consists of slow or rapid cooling, an acetic acid solvate is obtained.
The application describes the polymorphic form of the levorotatory enantiomer of modafinil designated CRL 40982 form II, characterized in that it produces an X-ray diffraction pattern comprising intensity peaks at lattice distances: 11.33; 8.54; 7.57; 7.44; 4.56; 3.78; 3.71 Å, the intensity peaks corresponding to lattice distances of: 8.54; 7.57; 7.44; 4.56; 3.78; 3.71 Å being particularly characteristic.
More precisely, the following X-ray diffraction spectrum, in which d represents the lattice spacing and I/I₀ the relative intensity:
| CRL 40982 FORME II | ||
| 2 Theta (degrés) | d (Å) | I/Io (%) |
| 11,6 | 11,33 | 54 |
| 15,4 | 8,54 | 58 |
| 17,4 | 7,57 | 41 |
| 17,7 | 7,44 | 34 |
| 23,3 | 5,67 | 19 |
| 24,8 | 5,33 | 26 |
| 27,4 | 4,83 | 19 |
| 28,9 | 4,59 | 36 |
| 29,1 | 4,56 | 97 |
| 29,8 | 4,45 | 23 |
| 32,8 | 4,05 | 29 |
| 34,3 | 3,88 | 23 |
| 35,3 | 3,78 | 100 |
| 35,9 | 3,71 | 40 |
| 40,1 | 3,34 | 21 |
| 47,7 | 2,83 | 20 |
| 53,7 | 2,53 | 32 |
| Diffractomètre: Miniflex Rigaku (Elexience) |
The application describes the polymorphic form of the levorotatory enantiomer of modafinil designated CRL 40982 form III, characterized by an X-ray diffraction pattern comprising lines of intensity at the following lattice distances d: 13.40; 12.28; 8.54; 7.32; 6.17; 5.01; 4.10; 3.97; 3.42; 3.20 Å, and the lattice distances: 12.28; 8.54; 5.01; 4.10; 3.97; 3.42; 3.20 Å corresponding to the most characteristic intensity lines.
In this context, the application particularly describes form III of (-)-modafinil producing the following X-ray diffraction pattern, in which d represents the lattice distance and I/Io the relative intensity:
| CRL 40982 FORME III | ||
| 2 Theta (degrés) | d (Å) | I/Io (%) |
| 9,8 | 13,40 | 40 |
| 10,7 | 12,28 | 39 |
| 15,4 | 8,54 | 100 |
| 18,0 | 7,32 | 33 |
| 21,4 | 6,17 | 23 |
| 25,9 | 5,11 | 26 |
| 26,4 | 5,01 | 87 |
| 29,6 | 4,48 | 26 |
| 29,9 | 4,44 | 20 |
| 31,1 | 4,27 | 34 |
| 31,7 | 4,19 | 20 |
| 32,4 | 4,10 | 77 |
| 33,1 | 4,02 | 23 |
| 33,5 | 3,97 | 64 |
| 36,5 | 3,66 | 38 |
| 39,1 | 3,42 | 40 |
| 41,9 | 3,20 | 32 |
| 46,4 | 2,91 | 23 |
| 52,7 | 2,58 | 25 |
| Diffractomètre: Miniflex Rigaku (Elexience) |
The application describes the polymorphic form of the levorotatory enantiomer of modafinil designated CRL 40982 form IV, characterized in that it produces an X-ray diffraction pattern comprising lines of intensity at lattice distances: 12.38; 8.58; 7.34; 6.16; 5.00; 4.48; 4.09; 3.66 Å, the most characteristic lines corresponding to lattice distances of 12.38; 8.58; 7.34; 5.00; 4.09 Å.
More specifically, form IV of (-)-modafinil is characterized in that it produces the following X-ray diffraction pattern, in which d represents the lattice distance and I/Io the relative intensity including lines of intensity at lattice distances:
| CRL 40982 FORME IV | ||
| 2 Theta (degrés) | d (Å) | I/Io (%) |
| 6,37 | 13,88 | 26 |
| 7,14 | 12,38 | 69 |
| 8,60 | 10,27 | 23 |
| 10,30 | 8,58 | 100 |
| 12,04 | 7,34 | 49 |
| 14,37 | 6,16 | 24 |
| 15,65 | 5,66 | 11 |
| 17,30 | 5,12 | 29 |
| 17,72 | 5,00 | 60 |
| 19,12 | 4,64 | 15 |
| 19,81 | 4,48 | 25 |
| 20,82 | 4,26 | 10 |
| 21,24 | 4,18 | 12 |
| 21,70 | 4,09 | 51 |
| 23,28 | 3,82 | 9 |
| 24,30 | 3,66 | 30 |
| 25,18 | 3,53 | 9 |
| 26,02 | 3,42 | 21 |
| 27,13 | 3,28 | 9 |
| 27,90 | 3,20 | 15 |
| Diffractomètre : Siemens AG. |
The application describes the polymorphic form of the dextrorotatory enantiomer of modafinil designated CRL 40983 form V, characterized in that it produces an X-ray diffraction pattern comprising lines of intensity at lattice distances: 9.63; 5.23; 5.03; 4.74; 4.66; 4.22; 4.10; 3.77 (Å).
| CRL 40983 FORME V | ||
| 2 Theta (degrés) | d (Å) | I/Io (%) |
| 6,65 | 13,27 | 22 |
| 7,24 | 12,21 | 5 |
| 9,17 | 9,63 | 51 |
| 10,38 | 8,51 | 19 |
| 12,28 | 7,20 | 15 |
| 14,33 | 6,17 | 14 |
| 15,81 | 5,60 | 4 |
| 16,95 | 5,23 | 68 |
| 17,64 | 5,03 | 100 |
| 18,69 | 4,74 | 51 |
| 19,03 | 4,66 | 58 |
| 20,06 | 4,42 | 3 |
| 21,06 | 4,22 | 91 |
| 21,67 | 4,10 | 64 |
| 22,39 | 3,97 | 17 |
| 23,61 | 3,77 | 55 |
| 24,64 | 3,61 | 8 |
| 25,40 | 3,50 | 13 |
| 26,21 | 3,40 | 20 |
| 26,95 | 3,31 | 18 |
| Diffractomètre : Bruker GADDS |
The application describes the dimethyl carbonate solvent of (-)-modafinil, characterized by the following diffraction pattern, in which d represents the lattice distance and I/Io the relative intensity:
| SOLVATE DE DIMETHYLCARBONATE | ||
| 2 Theta (degrés) | d (Å) | I/Io (%) |
| 7,17 | 12,31 | 38 |
| 9,12 | 9,69 | 29 |
| 9,72 | 9,09 | 16 |
| 10,35 | 8,54 | 35 |
| 12,17 | 7,27 | 100 |
| 14,25 | 6,21 | 16 |
| 16,26 | 5,45 | 10 |
| 17,36 | 5,10 | 13 |
| 17,72 | 5,00 | 21 |
| 18,35 | 4,83 | 9 |
| 19,16 | 4,63 | 9 |
| 19,88 | 4,46 | 14 |
| 21,04 | 4,22 | 12 |
| 21,49 | 4,13 | 25 |
| 21,73 | 4,09 | 24 |
| 23,49 | 3,78 | 22 |
| 24,55 | 3,62 | 35 |
| 25,24 | 3,53 | 8 |
| 26,05 | 3,42 | 9 |
| 26,88 | 3,32 | 7 |
| 27,48 | 3,24 | 13 |
| 27,81 | 3,21 | 10 |
| 28,79 | 3,10 | 8 |
| Diffractomètre : Siemens AG. |
The application describes the acetate solvent of the levorotatory and dextrorotatory enantiomers of modafinil which can be obtained according to the crystallization process of the invention, characterized in that it produces an X-ray diffraction pattern comprising intensity lines at lattice distances: 9.45; 7.15; 5.13; 4.15; 3.67 (Å).
| SOLVATE D'ACIDE ACETIQUE | ||
| 2-Theta (degrés) | d (Å) | I/Io % |
| 6,64 | 13,30 | 8,5 |
| 7,15 | 12,35 | 15 |
| 9,36 | 9,45 | 100 |
| 10,43 | 8,48 | 6,5 |
| 12,38 | 7,15 | 25 |
| 14,38 | 6,16 | 15 |
| 16,37 | 5,41 | 8 |
| 17,29 | 5,13 | 28 |
| 17,82 | 4,97 | 21 |
| 18,24 | 4,86 | 16 |
| 18,96 | 4,68 | 7 |
| 19,24 | 4,61 | 6 |
| 20,09 | 4,42 | 20 |
| 21,40 | 4,15 | 75 |
| 22,55 | 3,94 | 21 |
| 23,42 | 3,80 | 7 |
| 24,25 | 3,67 | 40 |
| 24,92 | 3,57 | 12 |
| 25,21 | 3,53 | 9,5 |
| 26,15 | 3,40 | 11 |
| 26,78 | 3,33 | 8 |
| 26,99 | 3,30 | 6 |
| 28,43 | 3,14 | 13 |
| 28,79 | 3,10 | 14 |
| 29,63 | 3,01 | 7 |
| 30,03 | 2,97 | 4 |
| 32,33 | 2,77 | 9 |
| 33,13 | 2,70 | 7 |
| 34,29 | 2,61 | 3 |
| 34,86 | 2,57 | 7 |
| 35,90 | 2,50 | 7 |
| Diffractomètre : Bruker GADDS |
The application describes a process for converting a first crystalline form of one enantiomer of modafinil into a second distinct crystalline form, said process comprising the steps of: i) suspending the crystalline form of said modafinil enantiomer in a solvent; ii) recovering the obtained crystalline form.
As solvents that may be suitable for this process, acetonitrile can be mentioned, among others.
In general, the initial crystalline form is kept in suspension at a temperature lower than the homogenization temperature for a sufficient period of time to allow complete conversion of the initial form. This duration may vary depending on the nature of the solvent, the initial crystalline form, and the temperature of the medium. Typically, the crystalline form is kept in suspension for at least 24 hours at room temperature, under atmospheric pressure, often for about 72 hours.
As an illustration, this process is implemented with (-)-modafinil.
In this context, according to a particular mode of implementing the request, the process uses form I in acetonitrile at step i), thereby obtaining an acetonitrile solvate of (-)-modafinil.
As an indication, form I is kept in suspension for several days, preferably for 3 days at room temperature and atmospheric pressure.
The application describes the acetonitrile solvent of (-)-modafinil which can be obtained according to the crystallization process of the invention. It is characterized by the following diffraction pattern, in which d represents the lattice spacing and I/Io the relative intensity:
| SOLVATE D' ACETONITRILE | ||
| 2 Theta (degrés) | d (Å) | I/Io (%) |
| 5,46 | 16,17 | 46 |
| 6,25 | 14,14 | 95 |
| 7,17 | 12,32 | 51 |
| 8,28 | 10,66 | 81 |
| 9,02 | 9,79 | 68 |
| 9,51 | 9,29 | 53 |
| 10,34 | 8,54 | 53 |
| 10,84 | 8,15 | 63 |
| 11,33 | 7,80 | 79 |
| 12,47 | 7,09 | 53 |
| 14,02 | 6,31 | 45 |
| 15,20 | 5,83 | 35 |
| 15,76 | 5,62 | 34 |
| 16,37 | 5,41 | 40 |
| 17,37 | 5,10 | 51 |
| 18,10 | 4,90 | 46 |
| 19,05 | 4,66 | 44 |
| 19,36 | 4,58 | 37 |
| 19,89 | 4,46 | 39 |
| 20,48 | 4,33 | 59 |
| 21,14 | 4,20 | 55 |
| 22,10 | 4,02 | 100 |
| 22,65 | 3,92 | 60 |
| 23,17 | 3,835 | 42 |
| 23,89 | 3,72 | 33 |
| 24,72 | 3,60 | 38 |
| 24,93 | 3,57 | 37 |
| 25,81 | 3,45 | 37 |
| 26,73 | 3,33 | 55 |
| 27,52 | 3,24 | 30 |
| 27,97 | 3,19 | 30 |
| 28,89 | 3,09 | 31 |
| 29,44 | 3,03 | 27 |
| Diffractomètre : Siemens AG. |
The application describes pharmaceutical compositions comprising the polymorphic forms CRL 40982 form II, CRL 40982 form III, CRL 40982 form IV, or CRL 40982 form V of (-)-modafinil, CRL 40983 form II, CRL 40983 form III, CRL 40983 form IV, and CRL 40983 form V, respectively, optionally in combination with a pharmaceutically acceptable vehicle.
These compositions can be administered orally, by mucosal routes (for example, ocular, intranasal, pulmonary, gastric, intestinal, rectal, vaginal, or via the urinary tract), or by parenteral routes (for example, subcutaneous, intradermal, intramuscular, intravenous, or intraperitoneal).
According to a preferred mode, the pharmaceutical compositions described in the application are administered orally in the form of tablets, pills, capsules, or immediate-release or controlled-release granules, as powder, capsules, liquid or gel suspensions, emulsions, or lyophilizates, more preferably in the form of tablets, capsules, liquid or gel suspensions. The dosage form may include one or more pharmaceutically acceptable excipients that are capable of ensuring the stability of the polymorphic forms (for example, a suspension of a polymorph in oil).
The pharmaceutical compositions described in the application include the polymorphic forms of (-)-modafinil and (+)-modafinil, forms II, III, IV or V, respectively, optionally mixed with each other and/or with one or more pharmaceutically acceptable excipients.
A solid formulation for oral administration is prepared by adding one or more excipients to the active ingredient, including a filler, and optionally a binder, a disintegrant, a lubricant, a surfactant and an emulsifier, a solubilizer, a coloring agent, a sugar substitute or a flavoring agent, and by shaping the mixture, for example, into the form of a tablet or a capsule.
Examples of excipients include lactose, sucrose, mannitol, or sorbitol; cellulosic preparations such as, for example, corn starch, rice starch, and potato starch.
Examples of binders include gelatin, acacia gum, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP), povidone, copovidone, dextran, dextrin, cyclodextrin and its derivatives such as hydroxypropyl-β-cyclodextrin.
Examples of sugar substitutes include aspartame, saccharin, and sodium cyclamate.
Examples of taste correcting agents include cocoa powder, mint in the form of herb, aromatic powder, mint in the form of oil, borneol, and cinnamon powder.
Examples of surfactants and emulsifiers include in particular polysorbate 20, 60, 80, sucrose ester (7-11-15), poloxamer 188, 407, PEG 300, 400, and sorbitan stearate.
Examples of solubilizing agents include Miglyol 810, 812, glycerides and their derivatives, and propylene glycol.
Examples of defoaming agents include, for example, polyvinylpyrrolidone, sodium carboxymethylcellulose, or alginic acid or a salt thereof such as sodium alginate.
Examples of lubricating agents include magnesium stearate, stearyl magnesium fumarate, behenic acid, and its derivatives.
The pharmaceutical compositions described in the application may also contain another crystalline form of (-)-modafinil or (+)-modafinil, respectively, notably form I and/or another active or inactive ingredient mixed with one or more other polymorphic forms of modafinil, such as form III, form II, form IV, and form V.
In the context of this application, the expression "pharmaceutically acceptable vehicle" covers solvents, dispersion media, antifungal and antibacterial agents, isotonic agents, and absorption-retarding agents. The use of such media and agents for pharmaceutically active substances is well known to those skilled in the art.
The application describes the use of CRL 40982 Form II, CRL 40982 Form III, CRL 40982 Form IV, or CRL 40982 Form V of (-)-modafinil, CRL 40983 Form II, CRL 40983 Form III, CRL 40983 Form IV, or CRL 40983 Form V of (+)-modafinil, respectively, for the manufacture of a drug intended for the prevention and/or treatment of a condition selected from hypersomnia, including notably idiopathic hypersomnia and hypersomnia in cancer patients treated with morphine analgesics to relieve pain; sleep apnea, excessive daytime sleepiness associated with a disease, obstructive sleep apnea, narcolepsy; somnolence,Excessive drowsiness, excessive drowsiness related to narcolepsy; central nervous system disorders such as Parkinson's disease; protection of brain tissue against ischemia; vigilance disorders, including those related to Steinert's disease; attention disorders, for example those related to hyperactivity (ADHD); fatigue state, particularly that related to multiple sclerosis and other degenerative diseases; depression, depressive state related to low sunlight exposure, schizophrenia, shift work, jet lag; eating behavior disorders;In which modafinil acts as an appetite stimulant, and the stimulation of cognitive functions at low doses.
The application describes a process for preparing the optical enantiomers of modafinil from (±)-modafinic acid, said process comprising the following steps: i) perform the resolution of the two optical enantiomers of (±)-modafinic acid and recover at least one of the enantiomers; ii) contact one of the two obtained enantiomers with a lower alkyl halofomate and an alcohol in the presence of a base; iii) recover the product obtained; iv) convert the ester obtained in step iii) into an amide; v) recover the product obtained in step iv).
Preferably, the lower alkyl haloformate is a lower alkyl chloroformate, and even more preferably, it is methyl chloroformate.
Advantageously, the lower alkyl halogenates, notably methyl chloroformate, used in this process to carry out the esterification of modafinic acid, are less toxic than dimethyl sulfate described in the prior art US 4,927,855 process for equivalent or improved yields. Therefore, the process is easier to implement and more suitable for industrial application.
Preferably, the reaction is carried out in the presence of an equimolar amount of lower alkyl haloformate and base relative to optically active modafinic acid at step ii).
It is particularly preferred to implement organic bases, more preferably nitrogenous bases.
Among the particularly preferred bases, one may notably mention triethylamine, diisopropylamine, diethylmethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
Preferably, the solvent used in step ii) is a lower aliphatic alcohol such as methanol, ethanol, or propanol, with methanol being particularly preferred.
According to a particular method of implementation, the ester obtained at the end of step ii) is crystallized by adding ice water.
The conversion of the ester to an amide in step iv) preferably consists of an ammonolysis, that is, treatment with ammonia.
In this context, it is generally preferable to operate with an excess of ammonia.
According to a preferred variant, the ammonia used is in gaseous form.
The ammonolysis reaction is preferably carried out in a polar solvent, preferably a protic one such as lower aliphatic alcohols, for example in methanol or ethanol, with methanol being particularly preferred.
The recoveries of the ester of (+) or (-) modafinic acid at step iii) and respectively of (+) or (-) modafinil at step iv) are carried out using conventional methods known to those skilled in the art.
The application describes a process for preparing the optical enantiomers of modafinil, comprising the following steps: a. carrying out the resolution of the two optical enantiomers of (±)-modafinic acid or its salts by means of a preferential crystallization process; b. converting the isolated enantiomer into an amide; c. recovering the enantiomer of modafinil obtained.
According to a preferred embodiment, step b) is carried out in two stages:
b1) convert said enantiomer into a lower alkyl ester;
b2) convert the product obtained in step b1) into an amide.
According to a particularly preferred mode of implementation, step b1) is carried out in the presence of an lower alkyl haloformate, an alcohol, and a base, under the conditions described previously.
According to a particularly advantageous method, when step b1) is carried out in the presence of methyl chloroformate, a base, and an alcohol, and step c1) consists of an ammonolysis as described previously, this process, in which the (±)-modafinic acid is resolved by preferential crystallization, generally gives a total yield of about 25%. Thus, the yield of the (-)-modafinic enantiomer obtained by this process, in particular, is significantly higher than that obtained in US Patent 4,927,855.
The preferential crystallization technique is a widely used technique in laboratories and industry.
This method is based on the alternating crystallization of two chiral compounds named R and S, forming a conglomerate in solvent A and within a given temperature range ΔT. This means that, within this temperature range, any mixture in thermodynamic equilibrium of the two enantiomers with the solution consists of two types of crystals, each containing only molecules of the same configuration, incorporating or not molecules of the solvent (solvates). The existence of such a conglomerate, without solid-state miscibility, will be implicitly accepted in what follows, at least within the temperature range ΔT and for solvent A.
Two classes of factors influence the crystallization of optical antipodes: on one hand, parameters related to ternary heterogeneous equilibria, and on the other hand, factors affecting the crystallization kinetics.
Parameters related to ternary heterogeneous equilibria include: the positions of crystallization layers of solid species that deposit at each temperature, and particularly the values of solubilities of stable and metastable phases, of the racemic mixture s(±), and of the enantiomers s(+) = s(-), as a function of temperature, and the ratio of solubilities α = s(±)/s(+); the extent of the stable and metastable domains of solid solutions, racemates, racemic solvates, active solvates, and polymorphic varieties of crystallized solids.
The factors influencing the crystallization kinetics include: internal factors related to the bonds between molecules, which are not changeable by the experimenter; and external factors that can be modified by the experimenter. These external factors include the nature of the solvent, the nature and concentration of impurities, the supersaturation achieved over time, the temperature interval ΔT, the speed and mode of agitation, the mass and particle size of the seeds, the wall effect, etc.
These two classes of factors directly influence the yield, the purity of the obtained phases, and the course of the separation operations. The feasibility of filtration will therefore depend on the particle size distribution and crystal habit, the viscosity of the suspension, the vapor pressure of the solvent, the supersaturation achieved by each enantiomer, and the possible presence of a metastable true racemate. These choices may also affect the kinetics of racemization of the enantiomers or the degradation of the molecule.
For each system consisting of the pair of antipodes (R and S) and the solvent (A), the factors influencing the kinetics are specific to each case.
There are mainly two types of preferential crystallization methods: on the one hand, the classical processes designated as SIPC for "Seeded Isothermal Preferential Crystallization" and their polythermal variants; on the other hand, the process designated as AS3PC for "Auto-Seeded Polythermic Programmed Preferential Crystallization."
In the preferential crystallization method AS3PC, also called self-seeding, the system is placed under conditions that allow it to generate its own seeds for the formation of the desired enantiomer. In contrast, in the SIPC method, these seeds are introduced by seeding. Both types of processes will be described in more detail below.
For more information regarding the preferential crystallization methods according to the AS3PC approaches, one may refer especially to the documents by G. Coquerel, M.-N. Petit and R. Bouaziz, Patent EP 0720595 B1, 1996; E. Ndzié, P. Cardinaël, A.-R. Schoofs and G. Coquerel, Tetrahedron Asymmetry, 1997, 8(17), 2913-2920; L. Courvoisier, E. Ndzié, M.-N. Petit, U. Hedtmann, U. Sprengard and G. Coquerel, Chemistry Letters, 2001, 4, 364-365.
According to a particular method of implementation, the process for doubling the optical enantiomers of (±)-modafinic acid or its salts is a seeded SIPC or S3PC process, said process comprising the following steps: a) homogenizing at a temperature TD an assembly composed of a racemic mixture of crystals in the form of a conglomerate, the first enantiomer of modafinic acid, and solvent, wherein the figurative point E, defined by the variables concentration and temperature TD, lies within the single-phase domain of the diluted solution; b) rapidly cooling the solution prepared in step a), initially at temperature TD, down to temperature TF; c) seeding the solution obtained in step b) during (i.e) either between TL and TF) or at the end of cooling (i.e., at TF) in very pure seeds of the first enantiomer; d) collect the crystals of the first enantiomer; e) add the racemic mixture of crystals in the form of a conglomerate to the mother liquors resulting from the collection performed in step d), and homogenize the new mixture by heating to a temperature TD, such that the figurative point E' is the symmetric of E with respect to the racemic mixing plane of the solvent system, antipode (-), antipode (+), said point E' being located in the single-phase domain of the diluted solution; f) rapidly cool the solution obtained in step e) initially at temperature TD,up to the temperature TF; g) seed the solution obtained in step f) with very pure germs of the second enantiomer; h) collect the crystals of the second enantiomer; i) add the racemic mixture in the form of a crystal conglomerate to the mother liquors resulting from the crystalline collection carried out in step h) and homogenize the new mixture by heating to a temperature TD to obtain a composition identical to that of the initial symbolic point E; j) repeat steps a), b), c), d), e), f), h), and j) to successively obtain the first then the second of the two enantiomers.
These two methods are often referred to as "SIPC" and "S3PC," the latter being a variant of SIPC, as described in detail in the following description.
In the following, according to the present application, the following terms are defined:
- TF denotes the temperature of the end of crystallization and filtration, located in the three-phase region;
- TL denotes the temperature for homogenizing the racemic mixture;
- TD denotes the starting temperature at which the initial mixture is a homogeneous solution;
- antipode denotes an enantiomer.
As a preferential process, the method for separating the two optical enantiomers of (±)-modafinic acid or their salts by preferential crystallization is an AS3PC self-seeding process, said process comprising the following steps: a) preparing a mixture composed of racemic crystals in the form of a conglomerate, of the first enantiomer of modafinic acid, and of solvent, wherein the figurative point E, defined by the variables concentration and temperature TB, lies within the two-phase domain of the enantiomer in excess, and is in equilibrium with its saturated solution; b) applying a temperature cooling programming law to the two-phase mixture prepared at step a).said programming law being such that the mother liquors maintain a low supersaturation which favors the growth of the enantiomer present in the form of crystals, while preventing the spontaneous nucleation of the second enantiomer present in the solution; c) adjust during the entire duration of the crystallization growth of step b) a slightly increasing agitation speed over time, so that it is always sufficiently slow to promote the growth of the first enantiomer while avoiding generating excessive stress forces that could cause uncontrolled nucleation, and sufficiently fast to achieve a homogeneous suspension and a rapid renewal of the mother liquor around each crystal of the first enantiomer; d) collect the crystals of the first enantiomer; e) add to the mother liquors resulting from the collection performed at step d) the racemic mixture of crystals in the form of a conglomerate,and bring the new set to a temperature TB for a duration sufficient to achieve thermodynamic equilibrium, so that the representative point E' is symmetric to E with respect to the racemic mixture plane of the solvent system, antipode (-), antipode (+), said point E' being located in the two-phase region of the second enantiomer in excess and in equilibrium with its saturated solution; f) apply the same cooling programming law as in step b) to the two-phase mixture prepared in step e) containing the second enantiomer, so that the mother liquors maintain a low supersaturation during crystallization in order to favor the growth of the enantiomer present in the form of crystals while preventing the spontaneous nucleation of the first enantiomer present in the solution; g) adjust,During the entire duration of the crystallization growth phase in step f), a slightly increasing agitation speed over time, such that it is, at any moment, sufficiently slow to promote the growth of the second enantiomer while avoiding the generation of excessive constraining forces that could cause uncontrolled nucleation, and sufficiently fast to ensure a homogeneous suspension and rapid renewal of the mother liquor around each crystal of the second enantiomer; h) collect the crystals of the second enantiomer; i) add the racemic mixture of crystals in the form of a conglomerate to the mother liquors resulting from the crystalline harvesting performed in step g) to obtain an assembly whose composition is identical to that of the initial assembly E; j) repeat steps a),b), c), d), e), f), g), h), and i) to sequentially obtain the first then the second of the two enantiomers.
In the following, in the context of this application, THOMO refers to the homogenization temperature of the mixture consisting of the racemic mixture, the first enantiomer, and the solvent.
Thus, at step (a) of the process described in the application, the selection of the solvent(s) and the working temperature range are defined in such a way as to simultaneously achieve: antipodes that form a conglomerate and whose possible racemate is metastable within the working temperature range; liquids that are sufficiently concentrated but with low viscosity and low vapor pressure; absence of solvolysis and racemization; and stability of the solvates if they are present at equilibrium and if they involve separable enantiomers.
At steps (a) and (e) of the process described in the application, the temperature TB is higher than the homogenization temperature TL of the racemic mixture contained in the initial suspension, and wherein, from the curve of THOMO as a function of enantiomeric excess and for a constant concentration of racemic mixture XL, said temperature TB is defined such that the mass of final crystals of the first enantiomer at steps (a) and (i) and of the second enantiomer at step (e), in equilibrium with their saturated solution, represents at most 50% and preferably between approximately 25% and 40% of the expected yield.
In steps (b) and (f) of the process described in the application, the temperature programming law for cooling from TB to TF, adapted to the experimental setup, is defined as follows: to obtain a low supersaturation throughout the entire crystallization period of the enantiomer initially present as crystals at the beginning of each cycle, this low supersaturation causing gentle secondary growth and nucleation; to reach at TF the maximum supersaturation of the other enantiomer without primary nucleation; to obtain crystal harvest at steps (d) and (h), which, after addition of a racemic mixture and compensation at steps (e) and (i), allows for the cyclic operation of the process.
Indeed, each experimental setup influences the supersaturation capacity of the mixtures used and the efficiency of agitation, and consequently, the cooling programming law is adapted to the specific conditions in which the process is carried out. However, the temperature TB, the solubility of the racemic mixture as a function of temperature, and the THOMO curve as a function of enantiomeric excess for a constant concentration in racemic mixture XL, are completely independent of the experimental setup.
The cooling programming law, which is the function relating temperature to time, is determined for its part from TL to TF by cooling the solution of concentration XL from TL + 1°C to TF, TF being lower than TL - (THOMO - TL), in order to obtain a stable saturated solution without primary nucleation while allowing for the doubling of the initial excess enantiomer, and wherein said cooling programming law is determined for its part from TB to TL by extrapolation of the same law determined from TL + 1°C to TF.
The preferential crystallization process of (±)-modafinic acid or its salts presents other advantageous characteristics, alone or in combination, such as: at steps (a) and (i), the mass of fine crystals of the first enantiomer in equilibrium with its saturated solution represents between approximately 25% and 40% of the expected yield, 50% being the maximum limit; at step (e), the mass of fine crystals of the second enantiomer in equilibrium with its saturated solution represents between approximately 25% and 40% of the expected yield, 50% being the maximum limit; at steps (b) and (f), the heat generated during the deposition of the first and second enantiomers is incorporated into the temperature programming law; at steps (e) and (i),Compensations are carried out in solvent; at steps (a), (e), and (i), the fine crystals of the racemic mixture in the form of a conglomerate that are added have undergone a prior treatment accelerating the dissolution step, such as grinding and sieving, sonication treatment, or partial freeze-drying; these treatments also aim to provide fine crystals capable of generating a high crystal growth surface; at steps (a), (e), and (i), which involve dissolution, the stirring speed is higher compared to steps (c) and (g).
In addition to the data on heterogeneous equilibria required to implement the AS3PC process, the operations remain subject to adjustable kinetic constraints, such as the cooling law, which are specific cases for each solvent/enantiomer combination.
According to one embodiment, the solvent used in step a) of the SIPC, S3PC or AS3PC processes is absolute or denatured ethanol, optionally in combination with an organic or mineral base, or with one or more solvents that may improve the solubility of the racemic mixture in ethanol.
As an alternative, the solvent used in step a) of the SIPC, S3PC, or AS3PC processes is 2-methoxyethanol or methanol, optionally in combination with an organic or mineral base, and/or one or more solvents, which may improve the solubility of the racemic mixture in ethanol.
According to a preferred embodiment, the solvent used in step a) of the SIPC or AS3PC process is ethanol, 2-methoxyethanol, or methanol. The filtration temperature TF is preferably between 0°C and 40°C for the (±)-modafinic acid.
In the case of ethanol, the TF temperature is preferably between 0°C and 25°C, and even better, it is close to 18°C or 17°C.
In the case of 2-methoxyethanol or methanol, the TF temperature is preferably between 20°C and 35°C, and notably close to 30°C.
Preferably, the concentration of the racemic mixture at step a) is between 2 and 50 wt%, more preferably between 2 and 30 wt%, and even better, close to 5.96 wt% in the case of ethanol, 15.99 wt% in the case of 2-methoxyethanol, and 25.70 wt% in the case of methanol.
In this context, it is particularly preferred that the enantiomeric excess at step a) is between 1 and 50% by weight, more preferably between 1 and 20% by weight, and even better, close to 11% by weight in the case of ethanol, 8% by weight in the case of 2-methoxyethanol, and 10% by weight in the case of methanol.
The TD temperature of the SIPC and S3PC processes, which is the temperature at which the initial mixture is a homogeneous solution, depends on the concentration and is generally between 35°C and 50°C under solvent reflux. Cooling the TD temperature down to TF is very rapid in order to remain in the single-phase domain and is preferably carried out in less than 20 minutes, for example by quenching.
According to a preferred method of the AS3PC process, the temperature TB is then between the temperatures TL and THOMO. The temperature TB can notably be between 25°C and 50°C.
For example, in the case of ethanol, when the enantiomeric excess is close to 11% by weight, the temperature TB is preferably between 25°C and 40°C, notably between 30.1°C and 36.2°C, and more preferably close to 33.5°C or 31.5°C.
In the case of 2-methoxyethanol, when the enantiomeric excess is close to 8% by weight, the temperature TB is preferably between 35°C and 50°C, notably between 39.1°C and 47.9°C, and more preferably close to 41°C.
In the case of methanol, when the enantiomeric excess is close to 10% by weight, the temperature TB is preferably between 40°C and 55°C, notably between 45.1°C and 53.9°C, and more preferably close to 46.5°C.
It is particularly preferred that the cooling of TB to TF at step b) be carried out over a sufficiently long period of time to allow for a significant average mass of the desired enantiomer crystals collected, but sufficiently short to prevent crystallization of the opposite enantiomer and thus achieve a high optical purity, especially above 85%. Cooling is therefore generally followed by polarimetry in order to determine the optimal moment for filtration. Preferably, the cooling period ranges from 50 to 70 minutes; even better, it is 60 minutes when the solvent used is ethanol.
Similarly, the duration of the temperature plateau at TF for the SIPC, AS3PC and S3PC processes is preferably sufficiently long to allow the collection of a high mass of desired enantiomer crystals, but not too long in order to prevent the counter-enantiomer from crystallizing simultaneously with the desired enantiomer, thereby achieving a high optical purity.
According to a preferred method, the duration of the TF temperature plateau is between 15 and 60 minutes, preferably approximately 60 minutes.
The professional operator can adjust the agitation speed according to the type of reactor used in the SIPC, S3PC, or AS3PC processes. As a guideline, for a 2 or 10-liter reactor, the agitation speed of the medium can be maintained between 150 and 250 revolutions per minute.
In a particularly interesting way, these preferential crystallization methods allow the isolation of the optical enantiomers of modafinil, notably the levorotatory enantiomer, with yields much higher than those obtained by resolution using a chiral agent. The yields achieved are generally around 90%, or even higher, compared to the optical enantiomer (+) or (−), which are typically around 45%, or more, compared to the racemic mixture.
The AS3PC and SIPC methods mentioned above are described below.
For example, the work by J. E. Ricci (Ed. Dover Publication Inc., New York, 1966, "The Phase Rule and Heterogeneous Equilibrium") deals with the general case of heterogeneous equilibria in ternary systems. The following description will be limited to the particular aspects of the ternary system: A (achiral solvent), R and S (non-racemizable enantiomers within the temperature range used), which are necessary for understanding the different preferential crystallization processes.
In order to highlight the particular role of the solvent, this ternary system will be represented using a right prism with an isosceles right triangle cross-section, with temperature plotted on an axis perpendicular to the concentration plane.
The identity of the thermodynamic variables of the two enantiomers: Tf (melting temperature), ΔHf (heat of fusion), solubility in an achiral solvent, etc., leads to a symmetric representation of the domains with respect to the vertical plane A-TS-T, which gathers the optically inactive mixtures shown in Figure 1. In order to facilitate a first description of this system, the following simplifications were adopted: only the pure components crystallize in a given arrangement (absence of racemates, solvates, and polymorphism for the enantiomers); the mutual solubility between the independent components is zero in the solid state; the solvent has a melting point significantly lower than that of the enantiomers; in the temperature range considered, the solubility of one enantiomer is not influenced by the presence of the other in the solution (Meyerhoffer's law is respected), which is represented by a value of the ratio α = 2.
Figure 1 allows to visualize the following phase domains: the single-phase domain of the diluted solution (φ = 1); the three crystallization layers of the components delimiting the two-phase domains (φ = 2).
The solvent deposition area is confined near point A, because the melting point of this component is significantly lower than that of the other components, in accordance with the previously mentioned conditions; the three univariant curves (φ = 3) or eutectic valleys derived from the binary eutectic points; the ternary eutectic invariant at Tε (φ = 4), below which all three components are crystallized.
Figure 2 shows two superimposed isothermal sections at TD and TF of the ternary system shown in Figure 1. At each temperature, the section is composed of four domains, as detailed in the table below.
| Température | Limite du domaine | Nature des phases à l'équilibre | Nombre de phases à l'équilibre |
| solution diluée | 1 | ||
| solution + cristaux de R | 2 | ||
| solutions + cristaux de S | 2 | ||
| solution + cristaux de R et S | 3 | ||
| solution diluée | 1 | ||
| solution + cristaux de R | 2 | ||
| solution + cristaux de S | 2 | ||
| solution + cristaux de R et S | 3 |
Figure 3 shows the isopleth section R-Y-T, which is fundamental in understanding the crystallization of ternary solutions under near thermodynamic equilibrium. The same section is also necessary for monitoring non-equilibrium processes, such as SIPC, its variants, and AS3PC. This plane is the geometric locus of points satisfying the relationship: with XA and XS giving the mass fractions of solvent and antisolvent S.
From Figure 3, we can distinguish the following:
- The single-phase domain of the ternary solution;
- The liquidus of the antipode R. This curve represents the intersection of the R-Y plane from Figure 2 with the crystallization sheet of this component. This curve of stable equilibrium originates from the melting of antipode R (not shown) and is limited at low temperatures by point L, which belongs to the ternary eutectic valley of racemic mixtures. This last curve and the trace of the cone at TL (horizontal segment at TL) delimit the two-phase domain: saturated solution plus crystals of R; it extends into the underlying three-phase domain along a metastable solubility curve of the same antipode R (dashed line);
- The three-phase domain: crystals of T and S;plus saturated solution. This area is bounded above by the horizontal trace of the cone of R, below by the trace of the invariant eutectic plane, on the left by the trace Lm of one of the cones related to the antipode S. The trace KL of the crystallization sheet of the antipode S which limits in the upper part the two-phase region: saturated solution plus crystals of S. This domain is bounded at its lower part by the traces of the two cones of S: gm and Lm. The location of this second trace Lm of the cone of S relative to the metastable solubility curve of R, the extension of EL, will be discussed later regarding the relative positions of F1 and F depending on the ratio of solubilities α; the ternary invariant at temperature Tε below which the three constituents crystallized A,R and S.
It is assumed in what follows that the overall system point (i.e., the representative point of the overall composition of the mixture) lies on the vertical line passing through point E in Figures 2 and 3. Its precise position is defined by its temperature (or ordinate). Only the following temperature range is considered: TD: temperature at which the initial mixture is a homogeneous solution, and TF: final crystallization and filtration temperature, located in the three-phase region.
This overall composition E corresponds to a slightly enriched racemic solution by a mass M of the R antipode, resulting in a total mass Mt (the enantiomeric excess R - S / R + S is generally between 4% and 9%). The equilibrium conditions are achieved by very slow cooling and by seeding with solid phase(s) as soon as the representative point of the mixture reaches a domain where this (these) phase(s) is (are) present at equilibrium.
At the initial temperature TD, the solution is homogeneous. Upon cooling, the following is observed successively: the crystallization of pure antipode R, and then THOMO until TL. At the same time, the solution point moves along the solubility curve of antipode R, from point E to the level THOMO, and then to point L inside the isopleth R-Y section. At point L, the mass M of crystals R in equilibrium with the saturated solution is given by Mt (XE − XL / 1 − XL) = M and corresponds to the enantiomeric excess present in the initial solution (Figure 3); the abscissas of points L, E, and R correspond to the compositions, and 1 (Figure 3). From TL onwards, the solution point evolves from L to IF along the univariant curve containing racemic composition solutions, shown in Figure 2, thus exiting the isopleth R-Y section of Figure 3; at this stage, crystals of R and S precipitate simultaneously and in equal amounts.
Duplication cannot be achieved under equilibrium conditions for temperatures below TL.
The previous E solution is homogenized at temperature TD (figures 4 and 5). In order to make it supersaturated, it is rapidly cooled to temperature TF without any crystallization appearing. This nonequilibrium solution is then seeded with very pure R antipode seeds of the same chirality as that of the excess antipode. The isothermal crystallization of the R antipode occurs, and the representative point of the solution evolves within the R-Y-T section of E at the level TF, where it initially coincides, until point F, where rapid filtration is performed. The mass of recovered R antipode is 2M, or equivalently equal to Mt (XE - XF / 1 - XF).
The previous fundamental operation thus created an F solution enriched with antipodes S. By adding a mass 2M of racemic mixture (equal to that of the recovered antipode) and heating this mixture to temperature TD, a homogeneous solution E' symmetric to E with respect to the vertical plane A-(RS)-T is obtained. The process allowing the obtaining of a mass 2M of antipode S will also be represented by a symmetric path relative to this median plane, as in the previous case. Therefore, the following operations are carried out sequentially: the homogeneous solution E' at temperature TD is first cooled to TF, then seeded with very pure seeds of antipode S; the growth of this antipode moves the representative point of the solution along the horizontal segment E'F' (at level TF); when the solution point coincides with F', the solution is filtered and provides a mass 2M of antipode S; after adding another mass 2M of racemic mixture and reheating to TD, a homogeneous solution is obtained again, whose representative point coincides with the initial point E at level TD; the rest of the process simply consists of repeating this cycle of operations.
Literature (Amiard, G., 1956, Bull. Soc. Chim. Fr. 447; Collet, A., Brienne, M. J., Jacques, J., 1980, Chemical reviews 80, 3, 215-30; Noguchi Institute, 1968, GB patent 1 197 809) is based on the previous general scheme; the main modifications that appeared in the literature are classified as follows: a) Spontaneous primary nucleation of the excess enantiomer During the resolution of (±)-threonine (Amiard, G., 1956, Bull. Soc. Chim. Fr. 447), the spontaneous primary nucleation of the excess enantiomer occurs within the homogeneous supersaturated solution. This primary nucleation takes place when the point E representing the overall composition is located in the three-phase region and the solution is not stirred (Collet,a) Seed growth during cooling (S3PC) This procedure is the most frequently encountered in the literature (Noguchi Institute, 1968, GB patent 1 197 809) when the process differs from SIPC. Among the procedures mentioned, differences appear; however, the following general steps can be identified: cooling of the homogeneous TD solution to a temperature lower than TL but higher than TF; seeding of the supersaturated homogeneous solution located in the three-phase region with seeds having the same chirality as that of the excess enantiomer; cooling down to TF.In some cases, this final step is controlled by a precise temperature programming (Noguchi Institute, 1968, GB patent 1 197 809).
These protocols will be grouped under the same term "S3PC" for "Seeded polythermic programmed preferential crystallization," although temperature programming is either nonexistent or limited to the second phase of cooling.
In order to better compare the classical methods and the AS3PC method, the initial point E is arbitrarily chosen on figures 6 and 7, same as in the previous case; however, as will appear in the following examples, the AS3PC process allows choosing a point E further away from the A-(RS)-T plane, and therefore with a higher enantiomeric excess, thus improving the crystal yield of each operation.
At the beginning of the process, and unlike classical protocols, the entire system, consisting of crystals and solution, is no longer homogenized but is brought to temperature TB. The initial solution is then in equilibrium with the excess enantiomer crystals (for example, R as shown in Figure 7). Therefore, the representative points of the solution (SE) and of the entire system (E) are not coincident at the beginning of the process. This two-phase mixture is subjected to a programmed temperature decrease without adding any crystal seeds. The representative point of the solution describes a curve SEF, contained within the R-Y-T plane, depending on the cooling kinetics (Figure 7). With a properly adjusted cooling rate, the growth of the excess enantiomer crystals starts initially, and the crystallization then evolves into a simultaneous regime of growth and secondary nucleation. When the representative point of the solution reaches point F, filtration is performed to recover a mass 2M of R antipode crystals.
Starting from point F, which corresponds to the previous mother solution, we move to point E', the symmetric of E with respect to the vertical plane A-(RS)-T, by adding a mass 2M of racemic mixture and heating at temperature TB. The enantiomeric excess is used to position ourselves in the two-phase domain containing the saturated solution and the crystals of the enantiomer in excess. Prior to this, the added racemic mixture during the transition from F to E' (as well as from F' to E) will be ground and sieved in order to accelerate the dissolution step of the two enantiomers, particularly that of the enantiomer in deficit, thus allowing the formation of a large number of crystals of the enantiomer in excess, which play the role of seeds introduced in conventional processes.
The saturated solution S'E, symmetric to SE with respect to the plane A-(RS)-T, is subject to the same cooling law. The crystals present from the beginning of cooling grow and then participate in a dual growth plus secondary nucleation mechanism. As in the case of the first crystallization, no seeding is therefore necessary.
Meanwhile, the representative point of the solution moves along a curve SE'F' contained in the plane of the isopleth section S-Y'-T, which is symmetric with respect to the bisector plane A-(RS)-T.
At the moment when the solution acquires the representative point located at F', filtration is carried out to collect a mass 2M of crushed and sieved racemic mixture, followed by a temperature increase to TB, which restores the initial two-phase equilibrium mixture.
The continuation of the process then involves repeating this cycle of operations, alternately yielding the R and S antipode crystals.
a) The equimolar mixture of the optical antipodes forms a conglomerate (pure antipodes or solvates) in the solvent used and for the temperature range TB - TF; however, the existence of a metastable racemate is not a disadvantage.
b) The molecules to be doubled are stable in this solvent and within the temperature range used between TB and TF.
c) A determination of the ternary equilibrium temperatures TL and THOMO is necessary. The temperature TL is the temperature at which the racemic mixture dissolves in the absence of any enantiomeric excess in the solution. Once TL is determined, the temperature THOMO corresponds to the temperature at which the solution becomes homogeneous.It depends on the initial enantiomeric excess and the α ratio of the solubilities of the racemic mixture and the antipode at TL. Knowledge of the supersaturation capacities of solutions between TL and TF is also necessary, depending on the cooling kinetics, agitation mode, nature of the vessel, and the particle size distribution of the excess antipode crystals. As a first approximation, the time of appearance of crystals by primary nucleation in the homogeneous racemic L solution cooled from a temperature slightly above TL with the same cooling rate gives an indication of the supersaturation capacity tolerated by the conglomerate under these experimental conditions.This way of operating has been taken into account in the examples. d) Knowledge of the dissolution kinetics of a known amount of racemic mixture (with a given particle size) dispersed in the solution at temperature TB. A few trials are sufficient to determine this duration.
In the following, examples and figures are provided for illustrative purposes of the present invention.
Figure 1 is a perspective representation of the ternary system solvent A - antipode R - antipode S, as a function of temperature, as well as the crystallization layers of each component and the compositions of doubly saturated solutions (univariant curves); on this figure are also shown the isotherms at temperatures TD and TF, and the ternary eutectic plane at temperature Tε containing four phases. Figure 2 is a projection onto the concentration plane of the equilibria at TD and TF, as well as a representation of the trace of the isopleth RY, on which point E represents the composition of the initial mixture slightly enriched in antipode R and destined to deposit the same antipode.Figure 3 is the vertical isopleth RY cross-section of Figure 2 containing the excess antipodal composition points and the initial solution E, on which the path of the solution point at equilibrium and cooling is shown for a mixture of composition XE (in bold line). For T < TL, the solution point no longer belongs to this cross-section. Figure 4 is a projection onto the concentration plane of the solution point path (in bold line) during the alternating doubling by isothermal entrainment at temperature TF and seeded according to the SIPC method. Figure 5 is the vertical isopleth cross-section containing the line RY from Figure 4 and illustrating the path of the solution point (in bold line) from E to F during isothermal (at TF) and seeded entrainment.According to the SIPC method. Figure 6 is a projection on the concentration plane of the path of the solution point (in bold line) during the doubling by the programmed and self-seeding polythermal process (AS3PC). Figure 7 is an isopleth vertical cross-section containing the line RY of Figure 6 and illustrating the path of the solution point (in bold line) from SE to F during the doubling by the programmed and self-seeding polythermal process (AS3PC). Figure 8 is a projection on the concentration plane of the path of the solution point (in bold line) during the doubling by the programmed and self-seeding polythermal process (AS3PC) and verifying the relation s(±) < 2 − α.All the isothermal and isoplethic cuts shown in these figures have composition variables expressed in mass fractions. Figure 9 shows the X-ray powder diffraction pattern corresponding to form II of the levorotatory and dextrorotatory enantiomers of modafinil, respectively (diffractometer: Miniflex Rigaku (Elexience)). Figure 10 shows the X-ray powder diffraction pattern corresponding to form III of the levorotatory and dextrorotatory enantiomers of modafinil, respectively (diffractometer: Miniflex Rigaku (Elexience)). Figure 11 shows the X-ray powder diffraction pattern corresponding to form IV of the levorotatory and dextrorotatory enantiomers of modafinil, respectively (diffractometer: Siemens AG).Figure 12 shows the X-ray powder diffraction pattern corresponding to the dimethyl carbonate solvate of the levorotatory and dextrorotatory enantiomers of modafinil, respectively (diffractometer: Siemens AG). Figure 13 shows the X-ray powder diffraction pattern corresponding to the acetonitrile solvate of the levorotatory and dextrorotatory enantiomers of modafinil, respectively (diffractometer: Siemens AG). Figure 14 shows the X-ray powder diffraction pattern corresponding to form V of the levorotatory enantiomer of modafinil (diffractometer: Bruker GADDS). Figure 15 shows the X-ray powder diffraction pattern corresponding to the acetic acid solvate of the levorotatory enantiomer of modafinil,The left-handed (levorotatory) and right-handed (dextrorotatory) forms of modafinil, respectively (X-ray diffractometer: Bruker GADDS). Figure 16 shows the X-ray powder diffraction pattern corresponding to the amorphous form of the levorotatory and dextrorotatory enantiomers of modafinil, respectively (X-ray diffractometer: Bruker GADDS).
The new crystalline forms of the modafinil enantiomers have been characterized respectively by powder X-ray diffraction spectroscopy, which provides a unique fingerprint characteristic of the studied crystalline form and allows distinguishing it from the amorphous enantiomers of modafinil and from any other crystalline form of the modafinil enantiomers.
X-ray diffraction data were measured using: a D5005 system as an X-ray powder diffractometer (Siemens AG, Karlsruhe, Germany, data analysis method Eva 5.0), with filtered copper nickel radiation of λ = 1.540 Å (with an acceleration voltage of 40 kV, tube current of 40 mA), with sample rotation during measurement (angle: 3 to 40° [2 theta]; at a speed of 0.04° [2 theta].s⁻¹, step size of 0.04°; sample preparation with preferred orientation). Using a Miniflex Rigaku (Elexience) system as an X-ray powder diffractometer,With chromium radiation, an accelerating voltage of 30 kV, a tube current of 15 mA, and sample rotation during measurement (angle: 3 to 80° [2θ]; at a speed of 0.05° [2θ]·s⁻¹, with a step size of 0.1°; sample preparation with preferred orientation). Using a GADDS system as an X-ray powder diffractometer (Bruker, Netherlands), equipped with a "Hi-Star area" detector and designed for 96-well plate analysis. The analyses were carried out at room temperature using copper CuKα radiation in the 2θ angle range between 3° and 42°.The diffraction pattern for each well is collected in two angular ranges (3° ≤ 2θ ≤ 21° and 19° ≤ 2θ ≤ 42°) with an exposure time between 50 and 250 seconds.
Of course, intensity values can vary depending on the sample preparation, the setup, and the measuring instruments. Measurement in 2θ can also be affected by instrument-related variations, so the corresponding peaks may vary by ±0.04° to ±0.2° depending on the equipment. Moreover, the expert will appreciate having access to lattice distances, which are essential data for diffraction spectra. Lattice distances are calculated using Bragg's law [(2d sin θ = nλ, where d = lattice distance (Å), λ = wavelength of copper radiation, θ = crystal rotation angle (in degrees)] when this relationship is satisfied.
a) The enantiomer I of modafinil was dissolved under reflux in polar solvents: methanol, absolute ethanol, absolute ethanol containing 3% water, denatured ethanol with toluene (2.5%) and containing 3% water, and water, according to the experimental conditions detailed in Table 1. Tableau 1
After rapid cooling by quenching in a water and ice bath for 30 minutes, the medium was filtered and dried in an oven at 35°C. The crystallized product was identified by its powder X-ray diffraction spectrum as the form I polymorph of the I-enantiomer of modafinil. b) The d-enantiomer of modafinil (555 g), treated under the same experimental conditions as Example 1 in a mixture of denatured ethanol and toluene (2 L) and water (0.1 L), crystallized in the form of polymorph I, as identified by its powder X-ray diffraction spectrum, with a yield of 91%.
| Solvant | Quantité de I-modafinil (g) | Volume de solvant (ml) | Rendement % |
| Méthanol | 8,37 | ≤ 50 | 63 |
| Ethanol absolu | 7,85 | 115 | 56 |
| Ethanol absolu + 3% d'eau | 5 | 70 | 54 |
| Ethanol dénaturé au toluène+ 3% d'eau | 5 | 70 | 56 |
| Eau | 5 | ≥ 400 | 88 |
a) 2 g of (-)-modafinil are suspended in acetone (20 ml) in a three-necked flask equipped with a condenser, a thermometer, and a stirrer. The mixture is heated under reflux. The reaction mixture is stirred for 30 minutes at approximately 56°C until complete dissolution of the (-)-modafinil. The solution is then slowly cooled at a rate of -0.5°C/min to 10°C under stirring. The reaction mixture is filtered, and the resulting solid is dried to obtain Form I of (-)-modafinil, identified by its X-ray diffraction spectrum. Yield: 62%.
b) The same experimental conditions applied to (+)-modafinil lead to the formation of an identical X-ray diffraction spectrum.
a) 1 g of (-)-modafinil is added to 7 ml of methanol heated under reflux until complete dissolution. The reaction mixture is precipitated by adding 6 ml of water at 1°C. The suspension is kept under stirring for 1 minute and then filtered through a sintered glass funnel (No. 3). The isolated solid is dried to obtain form I of (-)-modafinil, identified by its X-ray diffraction spectrum. Yield: 55%.
b) The same experimental conditions applied to (+)-modafinil result in an identical X-ray diffraction spectrum.
a) 2.5 g of (-)-modafinil are added to 90 ml of heated methanol under reflux until complete dissolution of the (-)-modafinil. The clear solution is added to 200 ml of water at 1°C and left without stirring for 10 minutes. The reaction mixture is filtered, and the recovered solid is dried to yield form I of (-)-modafinil, identified by its X-ray diffraction spectrum. Yield: 78%.
b) The same experimental conditions applied to (+)-modafinil lead to the formation of an identical X-ray diffraction spectrum.
a) In a 50 mL flask, 20 mL of 1,4-dioxane is introduced and heated under reflux. 2 g of (-)-modafinil are added to achieve saturation; magnetic stirring is ensured at 300 rpm. The whole system is cooled after complete dissolution of (-)-modafinil using a cooling ramp of -0.5°C/min down to 20°C. The obtained crystals are filtered on a sintered glass and identified as form I by their X-ray diffraction spectrum. Yield: 51%.
b) Applying the same experimental conditions to (+)-modafinil leads to an identical X-ray diffraction spectrum.
a) In a 250 mL flask, 180 mL of a mixture of ortho-, meta-, and para-xylene are introduced and heated under reflux. 0.5 g of (-)-modafinil are added to achieve saturation; magnetic stirring is used at 300 rpm. The entire mixture is cooled after complete dissolution of (-)-modafinil using a cooling ramp of -0.5°C/min down to 15°C. The resulting crystals are filtered on a sintered glass funnel and identified as form I by X-ray diffraction pattern. Yield: 26%.
b) Applying the same experimental conditions to (+)-modafinil leads to an identical X-ray diffraction pattern.
a) In a 250 mL flask, 100 mL of ethyl acetate is introduced and heated under reflux; 2 g of (-)-modafinil are added to achieve saturation; magnetic stirring is performed at 300 rpm. The entire system is cooled after complete dissolution of (-)-modafinil using a cooling ramp of -0.5°C/min until reaching 20°C. The obtained crystals are filtered through a sintered glass funnel and identified as form I by X-ray diffraction spectrum. Yield: 66%.
b) The (+)-modafinil (3 g) was dissolved under reflux in ethyl acetate (100 mL). After cooling by quenching in an ice-water bath for 30 minutes, the mixture was filtered and dried in an oven at 50°C under vacuum. The crystallized product was identified as the form I polymorph of (+)-modafinil by its powder X-ray diffraction pattern.
a) The CRL40982 form IV (0.5 g) and CRL40982 form II (0.5 g) convert to form I upon heating at 100°C. Moreover, pure form I of (-)-modafinil can be prepared by recrystallization of a mixture of (-)-modafinil form I (0.5 g), form II (0.5 g), and form III (0.5 g) in acetone (20 ml) for a sufficient period of time to achieve complete transformation (3 days). In both procedures, form I was identified by its X-ray powder diffraction pattern.
b) The use of (+)-modafinil (CRL 40983) under the same conditions leads to the same results.
a) 1 g of acetonitrile solvate of (-)-modafinil heated to 100°C for 8 hours transforms into a white solid identified as (-)-modafinil form I by its powder X-ray diffraction spectrum.
b) The use of (+)-modafinil (CRL 40983) under the same conditions leads to the same results.
a) 1 g of the monomethyl carbonate solvate of (-)-modafinil heated at 110°C for 16 hours transforms into a white solid identified as (-)-modafinil form I by its powder X-ray diffraction pattern.
b) The use of (+)-modafinil (CRL 40983) under the same conditions leads to the same results.
a) The enantiomer I of modafinil was dissolved under reflux in solvents: ethyl acetate, isopropanol, n-propanol, and denatured ethanol in toluene (2.5%), according to the experimental conditions detailed in Table 2. Tableau 2
After cooling by quenching in an ice-water bath for 30 minutes, the medium was filtered and dried in an oven at 35°C. In each experimental procedure, the crystallized product was identified by its powder X-ray diffraction spectrum as the form II polymorph (CRL40982 form II) of the I-enantiomer of modafinil. b) The D-enantiomer of modafinil (3.02 g) was dissolved in 100 ml of isopropanol under reflux, then cooled by quenching in an ice-water bath for 30 minutes, filtered, and dried under vacuum in an oven at 50°C. Under these experimental conditions, the (+)-modafinil crystallized in the form of polymorphic form II (CRL40983 form II), identified by its powder X-ray diffraction spectrum.
| Solvant | Quantité de I-modafinil (g) | Volume de solvant (ml) | Rendement % |
| Acétate d'éthyle | 6,33 | 385 | 53 |
| Isopropanol | 8 | 110 | 69 |
| n-propanol | 7,85 | 65 | 70 |
| Ethanol dénaturé au toluène (2,5 %) | 5 | 80 | 54 |
a) In a 250 mL flask, 100 mL of isopropanol is introduced and heated under reflux. Then, 3 g of (-)-modafinil are added to achieve saturation. The mixture is stirred using a magnetic stirrer (300 rpm). After complete dissolution of (-)-modafinil, the solution is slowly cooled to 20°C at a cooling rate of -0.5°C/min. The obtained crystals are filtered using a sintered glass funnel. The crystallized product was identified by its X-ray powder diffraction spectrum as the form II polymorph (CRL40982 form II) of the I-enantiomer of modafinil. Yield: 42%.
b) Applying the same experimental conditions to (+)-modafinil leads to the obtaining of an identical X-ray diffraction spectrum.
a) The enantiomer I of modafinil (5 g) is dissolved under reflux in 90 ml of acetone. After rapid cooling by quenching in an ice-water bath for 30 minutes, the mixture is filtered and dried in an oven at 35°C. The crystallized product was identified by its powder X-ray diffraction spectrum as the polymorph of form III of the I-enantiomer of modafinil. Yield: 61%.
b) The same experimental conditions applied to (+)-modafinil result in an identical X-ray diffraction spectrum.
a) In a 50 mL flask, 20 mL of chloroform is introduced and heated under reflux. 1.5 g of (-)-modafinil is added to achieve saturation; magnetic stirring is carried out at 300 rpm. The entire mixture is slowly cooled after complete dissolution of (-)-modafinil using a cooling ramp of -0.5°C/min down to 20°C. The resulting crystals are filtered on a fritted glass funnel and identified as (-)-modafinil form IV by its powder X-ray diffraction spectrum.
b) Applying the same experimental conditions to (+)-modafinil leads to the formation of an identical X-ray diffraction pattern.
a) In a 250 mL flask, 100 mL of methyl ethyl ketone is introduced and heated under reflux. 2 g of (-)-modafinil are added to achieve saturation; magnetic stirring is used at 300 rpm. The entire mixture is slowly cooled after complete dissolution of the (-)-modafinil using a cooling ramp of -0.5°C/min down to 20°C. The resulting crystals are filtered on a sintered glass funnel and identified as (-)-modafinil form IV by its powder X-ray diffraction spectrum.
b) Applying the same experimental conditions to (+)-modafinil results in an identical X-ray diffraction pattern.
In a 50 mL flask, 20 mL of tetrahydrofuran is introduced and heated under reflux. 1 g of (-)-modafinil is added to reach saturation; magnetic stirring is carried out at 300 rpm. The whole system is cooled slowly after complete dissolution of (-)-modafinil, using a cooling ramp of -0.5°C/min until reaching 10°C. The obtained crystals are filtered on a fritted glass filter and identified as (-)-modafinil form IV by its powder X-ray diffraction spectrum.
A methanolic solution of the D-enantiomer of modafinil (150 mg/ml) is distributed into a 96-well plate, and the methanol is then evaporated under reduced pressure before adding 25 µL of various solvents (concentration = 3.75 mg/25 µL of solvent) at room temperature. The multiwell plates are made of stainless steel (316 L), and each sealed well contains a total volume of 50 µL. The plate is heated up to an initial temperature of 60°C according to a temperature gradient of 4.8°C/min. After 30 minutes, the plate is cooled slowly (-0.6°C/min) or rapidly (-300°C/min) until a final temperature of 3°C is reached, and then it is kept at this final temperature for a minimum of 1 hour or a maximum of 48 hours. The solvent is evaporated under vacuum (nitrogen atmosphere), and the crystallized product is analyzed.
The d-modafinil crystallized in 2-propanone under the operating conditions described above, by slowly cooling (-0.6°C/min) and maintaining the temperature at 3°C for 1 hour. The crystals were identified as (+)-modafinil form V (CRL40983 form V) by their powder X-ray diffraction pattern.
The d-modafinil crystallized in THF under the above-mentioned operating conditions, by rapidly cooling to -300°C/min and maintaining the temperature at 3°C for 1 hour. The crystals were identified as (+)-modafinil form V (CRL40983 form V) by their powder X-ray diffraction pattern.
a) 2 g of (-)-modafinil are added to 20 ml of dimethyl carbonate and heated under reflux. The reaction mixture is stirred for 10 minutes until complete dissolution of the (-)-modafinil. The solution is then slowly cooled (-0.5°C/min) to 10°C with stirring. The reaction mixture is subsequently filtered through a fritted glass funnel (No. 3). The analysis of the modafinil dimethyl carbonate solvate shows a mass loss of approximately 24% from about 50°C to 110°C. Therefore, the stoichiometry of the dimethyl carbonate solvate is 1:1. This is therefore a true solvate, identified as the dimethyl carbonate solvate of (-)-modafinil by its powder X-ray diffraction spectrum. Yield: 88%.
b) The same experimental conditions applied to (+)-modafinil result in an identical X-ray diffraction spectrum.
a) Polymorphic I crystals of (-)-modafinil are suspended in acetonitrile for 3 days at 20°C. The recovered solid is identified as an acetonitrile solvate by X-ray diffraction. The solvate corresponds to a true solvate with stoichiometry: 1-1, identified as the acetonitrile solvate of (-)-modafinil by its X-ray powder diffraction pattern. Yield 92%.
b) Applying the same experimental conditions to (+)-modafinil leads to the obtaining of an identical X-ray diffraction spectrum.
a) 75 mg of d- or l-modafinil were suspended in acetic acid in Minimax reactors to obtain a concentration of 15% (weight/volume). The crystallization medium, under constant stirring, was heated to an initial temperature of 60°C or 80°C according to a temperature gradient of 3°C/min. After 30 minutes, the medium was cooled slowly (-0.6°C/min) or rapidly (-300°C/min) until a final temperature of 3°C was reached, then kept at this final temperature for a minimum of 1 hour or a maximum of 48 hours. Under these experimental conditions, the acetic acid solvate was obtained and identified by its powder X-ray diffraction spectrum.
b) The same experimental conditions applied to (+)-modafinil result in an identical X-ray diffraction spectrum.
The solvate of (-) or (+) modafinil obtained in Example 20 was converted into the amorphous form by heating at 120°C for 3 hours. The powder X-ray diffraction spectrum obtained is shown in Figure 16.
- Solubility of the racemic mixture in ethanol:
- Purity antipode (+) solubility = 1.99% at 20°C; α ratio = 2.06 - Coordinates of point L = Concentration: 5.96%; temperature: 30°C
| Température (°C) | 10,0 | 20,0 | 30,0 |
| Solubilité massique (%) | 3,0 | 4,1 | 5,96 |
| Excès énantiomérique | 0 | 3,94 | 7,66 | 11,1 |
| 32,4 | 34,5 | 36,3 |
By setting TB closer to TL, about 40% of the final harvest in the form of fine crystals can thus be obtained at the beginning of the experiment, leaving only 60% of the expected final mass to be produced. This operation is easy to perform when the Z ratio is sufficiently high (greater than or equal to 0.8 for a given enantiomeric excess percentage).
In the case of modafinil acid, crystallization occurs properly. TB1 temperature = 33.5°C and TB2 temperature = 31.5°C. TF temperature = 17°C. Cooling law = T = f(t) Loi de refroidissement de type I
Loi de refroidissement de type II
| Température (°C) | 33,5 | 17 | 17 |
| t (min) | 0 | 60 |
| Température (°C) | 31,5 | 17 | 17 |
| t (min) | 0 | 60 |
In both cases, starting from TB1 or TB2, the cooling law is a linear segment: followed by a plate at 17°C.
Enantiomeric excess = 11%
Plateau duration at TB1 or TB2 = 30 minutes. Agitation speed = 200 rpm.
| Masse de solvant | Masse (±) (g) | Masse (+) (g) | Loi de refroidissement |
| 38,38 | 2,43 | 0,3 | Type 1 |
| N° | Masse d'antipode pur (g) | Pureté optique (%) |
| 1 | 0,61 | (+) 90,7 |
| 2 | 0,65 | (-) 89,4 |
| 3 | 0,68 | (+) 90,5 |
| 4 | 0,64 | (-) 90,6 |
| 5 | 0,65 | (+) 88,8 |
| 6 | 0,72 | (-) 91,5 |
| 7 | 0,71 | (+) 92,8 |
Initial enantiomeric excess = 11%
Agitation speed = 200 rpm
| Masse de solvant | Masse (±) (g) | Masse (+) (g) | Loi de refroidissement |
| 511 | 32,42 | 3,99 | Type I |
| N° | Masse d'antipode pur (g) | Pureté optique (%) |
| 1 | 8,41 | (+) 89,4 |
| 2 | 8,69 | (-) 90,7 |
| 3 | 8,57 | (+) 89,8 |
Initial enantiomeric excess = 11.1%
| Masse de solvant | Masse (±) (g) | Masse (+) (g) | Loi de refroidissement |
| 1874 | 118,4 | 14,84 | Type I |
| N° | Masse d'antipode pur (g) | Pureté optique (%) |
| 1 | 32,1 | (+) 89,1 |
| 2 | 32,3 | (-) 90,3 |
| 3 | 32,5 | (+) 91,2 |
| 4 | 32,9 | (-) 89,7 |
| 5 | 33,1 | (+) 90,3 |
| 6 | 32,7 | (-) 90,7 |
| 7 | 32,9 | (+) 90,6 |
Initial enantiomeric excess = 11.7%
Agitation speed = 200 rpm throughout the process with an Impeller® agitation motor
| Masse de solvant | Masse (±) (g) | Masse (+) (g) | Loi de refroidissement |
| 6481 | 408 | 51,32 | Type I ou II |
| N° | Masse d'antipode pur (g) | Pureté optique (%) | Durée d'un cycle | Loi de refroidissement |
| 1 | (+)121,9 | 90,5 | 103 | I |
| 2 | (-) 121,1 | 92,2 | 104 | I |
| 3 | (+) 137,6 | 91,3 | 83 | II |
| 4 | (-) 134,7 | 90,8 | 84 | II |
| 5 | (+) 135,1 | 90,6 | 83 | II |
| 6 | (-) 134,5 | 91,2 | 82 | II |
- Solubility in 2-methoxyethanol of the racemic mixture:
- Solubility of pure antipode (+) = 4% at 20°C; α ratio = 2.53 - Coordinates of point L = Concentration: 16%; temperature: 39.4°C
| Température (°C) | 10,0 | 20,0 | 30,0 | 40,0 |
| Solubilité massique (%) | 7,4 | 8 | 13,5 | 16 |
| Excès énantiomérique | 0 | 4% | 6% | 8% |
| 44 | 46 | 48 |
Enantiomeric excess = 10%Initial temperature TB: 41 °CFiltering temperature TF: 30 °CLinear temperature ramp from 41°C to 30°C in 1 hour
Agitation speed = 200 rpm
| Masse de solvant | Masse (±) (g) | Masse (+) (g) |
| 8000g | 1523 | 132 |
| N° | Masse d'antipode pur (g) | Pureté optique (%) |
| 1 | 269.86 | (+) 100 |
| 2 | 300 | (-) 97 |
| 3 | 348.68 | (+) 100 |
| 4 | 369.2 | (-) 99.97 |
| 5 | 413.97 | (+) 100 |
| 6 | 453.2 | (-) 95.5 |
| 7 | 423.8 | (+) 98 |
| 8 | 456 | (-) 99.7 |
| 9 | 494.6 | (+) 99.3 |
| 10 | 485.4 | (-) 100 |
| 11 | 517 | (+) 92 |
| 12 | 487.97 | (-) 95.9 |
| 13 | 471.24 | (+) 99.5 |
According to the AS3PC method in methanol • Conditions related to equilibria - Solubility in methanol of the racemic mixture:
- Purity of the antipode (+): solubility = 4.9% at 20°C; α ratio = 2.53 - Coordinates of point L = Concentration: 25.6%; temperature: 46.5°C
| Température (°C) | 10,0 | 20,0 | 30,0 | 40,0 |
| Solubilité massique (%) | 7,4 | 9,7 | 13,9 | 25,7 |
| Excès énantiomérique | 0 | 4% | 6% | 8% | 10% |
| 50 | 52 | 53 | 54 |
Enantiomeric excess = 10%Initial temperature TB: 46.5°CFiltration temperature TF: 30°CCooling ramp: linear from 39.4°C to 18°C over 1 hour.
Agitation speed = 230 rpm
| Masse de solvant | Masse (±) (g) | Masse (+) (g) |
| 1450g | 501,5 | 55,7 |
| N° | Masse d'antipode pur (g) | Pureté optique (%) |
| 1 | 107,1 | (+) 99,7 |
| 2 | 90,9 | (-) 78,2 |
| 3 | 137,1 | (+) 72,7 |
| 4 | 125,5 | (-) 84,1 |
| 5 | 95,9 | (+) 94,0 |
| 6 | 91,6 | (-) 88,6 |
| 7 | 87,0 | (+) 85,7 |
| 8 | 92,2 | (-) 88,1 |
| 9 | 107,0 | (+) 104,2 |
| 10 | 130,6 | (-) 120,7 |
| 11 | 159,9 | (+) 111,0 |
| 12 | 123,3 | (-) 113,8 |
| 13 | 133,0 | (+) 130,3 |
| 14 | 143,0 | (-) 134,7 |
| 15 | 139,2 | (+) 128,5 |
| 16 | 159,4 | (-) 127,5 |
| 17 | 114,0 | (+) 111,5 |
| 18 | 123,4 | (-) 120,9 |
| 19 | 180,6 | (+) 99,3 |
| 20 | 114,2 | (-) 110,9 |
| 21 | 123,1 | (+) 120,6 |
| 22 | 118,4 | (-) 115,0 |
| 23 | 140,1 | (+) 135,9 |
| 24 | 186,2 | (-) 118,6 |
| 25 | 157,1 | (+) 106,8 |
| 26 | 121,2 | (-) 102,2 |
| 27 | 126,5 | (+) 122,5 |
| 28 | 106,6 | (-) 99,0 |
Initial enantiomeric excess = 11.8 % Temperature at which the initial mixture is a homogeneous solution TD = 40°C.
- Time (hold) at TF before introducing the microbes = 0 minutes - Mass of microbes = 1% - Crystallization time = as fast cooling as possible by quenching. Agitation speed = 200 rpm throughout the process with an Impeller® agitator.
| Masse de solvant | Masse (±) (g) | Masse (+) (g) | Loi de refroidissement |
| 1874 | 118,4 | 14,84 | 20 mn de 40°C à 17°C = température d'ensemencement |
| N° | Masse d'antipode pur (g) | Pureté optique (%) |
| 1 | 30,9 | (+) 90,4 |
| 2 | 31,5 | (-) 90,7 |
| 3 | 31,3 | (+) 91,4 |
| 4 | 31,2 | (-) 90,9 |
| 5 | 31,6 | (+) 91,5 |
- Initial enantiomeric excess: 11.14%
- Seed temperature = 29°C - Seed mass = 1% - Crystallization time = as fast cooling as possible by quenching. Agitation speed = 200 rpm throughout the process with an Impeller® agitation system.
| Masse de solvant | Masse (±) (g) | Masse (+) (g) | Loi de refroidissement |
| 1874 | 118,4 | 14,84 | 20 mn de 40°C à 17°C |
| N° | Masse | Pureté optique (%) avant purification |
| 1 | 25,2 | (+) 84,5 |
| 2 | 24,9 | (-) 85,6 |
| 3 | 25,6 | (+) 84,6 |
| 4 | 25,2 | (-) 85,3 |
| 5 | 24,9 | (+) 85,8 |
This step is illustrated by the implementation of (-)-modafinil.
In a 10-liter flask, 3.3 liters of acetone, 0.6 liter of water, 349 g of Na2CO3 (3.29 moles), and 451 g of (-)-modafinic acid (1.64 moles) are charged, and the mixture is heated to reflux. Then, 330 ml of dimethyl sulfate (3.29 moles) is added over half an hour. The reflux is continued for one hour, and then the reaction mixture is allowed to return to ambient temperature over 20 hours.
Then, the medium is poured over 6.6 kg of ice. Crystallization is immediate, and after an additional 3 hours of stirring, a filtration yields a white precipitate, which is washed in 6 liters of water.
The product is then remixed with 6 liters of water and filtered again. The precipitate is dried under vacuum at 35°C, resulting in 436.3 g of methyl ester (Yield = 92.3%).
In 450 ml of methanol, 100 g of (-)-modafinic acid (0.36 mole) and 21.6 ml of triethylamine (0.36 mole) are introduced. After the salt has dissolved, 30 ml of methyl chloroformate (0.36 mole) is gradually added to the resulting solution.
The reaction takes place in 15 minutes by heating from 28°C to 35°C (release of CO2). It is left to stir for 2 hours and then poured onto crushed ice + water (500 g / 500 ml). The ester crystallizes; after filtration and drying, 94.5 g of ester is obtained (Yield = 90.1%).
In a 4-liter double-walled reactor, 1.63 liters of denatured methanol in toluene, 0.1 liter of water, and 425.1 g of methyl ester (1.474 moles) are charged.
The temperature is raised to 30°C, and ammonia sparging is started while maintaining this temperature. This operation lasts 1 hour and 45 minutes, and the amount of ammonia introduced is 200 g. The agitation is maintained for 21 hours and 30 minutes, then cooling is performed by setting the target temperature to 0°C.
The medium is then filtered through a sintered glass funnel number 3, yielding 57.2 g of the first fraction and a filtrate which is evaporated to dryness. The residue is taken up with 1.2 liters of denatured ethanol in toluene, and after filtration, a second fraction of 308.6 g is obtained.
The two jets are combined and recrystallized in 1.83 liters of denatured ethanol with toluene. A hot filtration yields a filtrate that, upon cooling, gives a product which is filtered and dried under vacuum at 30°C. A total of 162.2 g of white product is obtained.
These 162.2 g are mixed with 810 ml of denatured ethanol and toluene, and then heated under reflux to obtain complete dissolution. It is then allowed to crystallize by cooling, filtered through a sintered glass funnel number 4, and dried under vacuum at 30°C. 147.3 g of (-)-modafinil (CRL 40982) is obtained. Yield = 36.6%.
Specific rotation = -18.6 (Solution at 4.9% in methanol) Melting point = 163°C.
Modafinil crystals were obtained in acetone. This phase has the following characteristics: Hexagonal P31 or P32 according to the enantiomer, therefore modafinil is a conglomerate; a = 9.55, b = 9.55, c = 13.14 Å, α = 90.000, β = 90.000, γ = 120.000°.
The diffracted intensities were measured using an automatic SMART APEX diffractometer (Brucker) at 20°C.
The structure was solved using the Saintplus, Sadabs, and Shelxs software packages.
It is worth noting the unusual nature of this space group for chiral organic molecules.
In the crystal lattice, the pattern repeats three times, meaning Z = 1. These molecules are connected to each other by hydrogen bonds, through the acid and sulfoxide functions. It can be noted that the strongest interactions (hydrogen bonds) wrap around the ternary helical axis following the crystallographic z-direction.
The crystal structure of the (+) modafinil form I, identified as identical to that of the (-) modafinil form I, has been determined. It possesses the following characteristics: Crystal system = monoclinic; Space group P2₁; a = 5.6938, b = 26.5024, c = 9.3346 Å; β = 105.970°.
The diffracted intensities were measured using an automatic SMART APEX diffractometer (Brucker) at 20°C.
Claims (14)
- Process for the preparation of a polymorphic form of the levorotatory or dextrorotatory enantiomer of modafinil, characterized in that it produces an X-ray diffraction spectrum comprising intensity lines at the lattice distances: 8.54, 4.27, 4.02, 3.98 (Å), said process comprising the following steps:i) dissolving one of the optical enantiomers of modafinil in a solvent chosen from methanol, ethanol, propanol, isopropanol, butanol, isobutanol, 2-methyl-2-pentanol, 1,2-propanediol, t-amyl alcohol, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, ethyl formate, diethyl ether, tetrahydrofuran, dioxane, dibutyl ether, isopropyl ether, t-butyl methyl ether, tetrahydropyran, chloroform, 1,2-dichloroethane, dichloromethane, chlorobenzene, ortho-, meta- and para-xylene, a mixture of ortho-, meta- and/or para-xylene, methoxybenzene, nitrobenzene, trifluorotoluene, toluene, acetone, methyl ethyl ketone, methyl isobutyl ketone, butan-2-one, cyclopentanone, isobutyl methyl ketone, 2-pentanone, 3-pentanone, acetic acid, pyridine, acetonitrile, propionitrile, 4-methylmorpholine, N,N-dimethylacetamide, nitromethane, triethylamine, N-methylpyrrolidone, heptane, 2,2,4-trimethylpentane, cyclopentane, cyclohexane, dimethyl carbonate, water and alcohol/water mixtures;ii) crystallizing the modafinil enantiomer;iii) recovering the crystalline form of the modafinil enantiomer thus obtained.
- Process according to Claim 1, in which the solvent used in step i) is chosen from acetone, ethanol, 1,4-dioxane, ethyl acetate, ortho-, meta- or para-xylene, mixtures of ortho-, meta- and/or para-xylene, methanol, water, and alcohol/water mixtures.
- Process according to Claim 1 or 2, in which the modafinil enantiomer is the levorotatory enantiomer.
- Process according to Claim 1 or 2, in which the modafinil enantiomer is the dextrorotatory enantiomer.
- Process according to any one of Claims 1 to 4, in which the crystallization is carried out under kinetic or thermodynamic conditions.
- Preparation process according to any one of Claims 1 to 5, in which the crystallization is carried out by precipitation, optionally in the presence of seeds of crystals in the desired crystalline form.
- Preparation process according to Claim 6, which uses methanol as solvent in said step i), and which implements a crystallization by precipitation by adding cold water as anti-solvent of the methanol.
- Preparation process according to any one of Claims 1 to 7, in which the crystallization implements a cooling of the solution obtained in step i).
- Process according to Claim 8, in which the cooling is slow.
- Process according to Claim 8, in which the cooling is rapid.
- Process according to Claim 9, in which the solvent used in step i) is chosen from acetone, ethanol, 1,4-dioxane, ethyl acetate, ortho-, meta- or para-xylene, or a mixture of ortho-, meta- and/or para-xylene.
- Process according to Claim 10, in which the solvent used in step i) is chosen from methanol, water and alcohol/water mixtures, such as ethanol/water and methanol/water mixtures.
- Process according to any one of the preceding claims, in which the polymorphic form is characterized in that it produces an X-ray diffraction spectrum comprising intensity lines at the lattice distances: 13.40, 8.54, 6.34, 5.01, 4.68, 4.62, 4.44, 4.27, 4.20, 4.15, 4.02, 3.98, 3.90, 3.80, 3.43 (Å).
- Process according to Claim 12, in which the polymorphic form is characterized as follows:
CRL 40982 FORM I 2 Theta (degrees) d (Å) I/Io (%) 9.8 ± 0.2 13.40 32 15.4 ± 0.2 8.54 87 20.8 ± 0.2 6.34 24 26.4 ± 0.2 5.01 14 28.3 ± 0.2 4.68 19 28.7 ± 0.2 4.62 16 29.9 ± 0.2 4.44 45 31.1 ± 0.2 4.27 100 31.6 ± 0.2 4.20 23 32 ± 0.2 4.15 14 33.1 ± 0.2 4.02 78 33.4 ± 0.2 3.98 84 34.1 ± 0.2 3.90 16 35.1 ± 0.2 3.80 15 39 ± 0.2 3.43 22
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| HK11112662.9A HK1158171B (en) | 2002-12-20 | 2005-12-15 | Crystalline form of the optical enantiomers of modafinil |
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| HK1078309B HK1078309B (en) | 2019-12-06 |
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